ABSTRACT Neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) are more prevalent in males than females, but to date, the molecular mechanisms that underlie sex bias in ASD and ID remain unknown. Until recently, sex had not been routinely considered in data analysis, and females were often excluded from behavioral experiments altogether. Thus, testing of sex differences in preclinical animal models of ASD/ID has been limited. The PI has found that loss of the signaling scaffold CC2D1A leads to male- specific disruptions in both intracellular signaling and social and cognitive behavior in transgenic mouse models. CC2D1A loss of function (LOF) mutations cause ID, ASD, aggressive behavior, and seizures in humans. In parallel, her group showed that Cc2d1a knock-out (KO) male mice display behavioral features of the human phenotype, while female KO mice only present with a subset of cognitive deficits. CC2D1A acts as a signaling scaffold upstream of Cyclic AMP response element binding protein (CREB), which has a critical role in neuronal differentiation, synaptic function, and learning and memory. Male Cc2d1a KO mice show a reduction in CREB signaling in the hippocampus, while no alterations in CREB signaling are found in females. The central hypothesis for this proposal is that CC2D1A controls male-specific CREB signaling in the developing and adult hippocampus, and that disrupted CREB signaling in males leads to altered plasticity and cognitive and affective phenotypes following loss of CC2D1A. The long-term goal of the PI is to define how sex-specific intracellular signaling selectively controls behavior in males and females, and how these mechanisms contribute to susceptibility to ASD and ID. The studies outlined in this proposal will 1) Define the cellular deficits linked to male-specific behavior in Cc2d1a- deficient mice by analyzing differences in spine density and LTP in males and females. 2) Show that impaired male-specific CREB signaling leads to behavioral deficits in Cc2d1a-deficient males by pharmacologically targeting phosphodiesterase 4D (PDE4D), a binding partner of CC2D1A which is upstream of CREB activation. 3) Identify how CC2D1A controls sex-specific CREB signaling by studying the localization and composition of the signaling complex assembled by CC2D1A in the male and female hippocampus. These studies will identify a novel sex-specific mechanisms for CREB signaling regulation, and link molecular and cellular deficits to impaired behavior. Thus, this work will provide key insight on sex-specific signaling in the brain, and lead to significant advances towards understanding mechanisms that could lead to male bias in neurodevelopmental disorders.